Why do we Validate?

In a recently posted warning letter, FDA cited a drug manufacturer for failing to validate the manufacturing process for tablets.  FDA collected three samples during the inspection and laboratory results identified that all three were sub-potent for the active ingredient and one of the samples failed for content uniformity.

One of the key reasons for validation is to understand the sources of variability in the manufacturing process and once known to control the variability in order to consistently produce products that meet specification.

Fundamentally this is addressed in the 3 stages of process validation:

  1. Stage 1 ― Process Design
  2. Building and Capturing Process Knowledge and Understanding
  3. Establishing a Strategy for Process Control
  4. Stage 2 ― Process Qualification
  5. Design of a Facility and Qualification of Utilities and Equipment
  6. Process Performance Qualification
  7. PPQ Protocol
  8. PPQ Protocol Execution and Report
  9. Stage 3 ― Continued Process Verification

As identified in the process validation guidance:

A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control of the manufacturing process that results in products with the desired quality attributes. Manufacturers should:

  • Understand the sources of variation
  • Detect the presence and degree of variation
  • Understand the impact of variation on the process and ultimately on product attributes
  • Control the variation in a manner commensurate with the risk it represents to the process and product

Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product.

Focusing exclusively on qualification efforts without also understanding the manufacturing process and associated variations may not lead to adequate assurance of quality. [italics added] After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.

One way to examine the manufacturing process is through the concept of Dominance as described in Juran’s Quality Handbook pages 4.14, 22.33, and control tools as identified in table 22.9.  For a brief summary see Application of Dominance to Validation.

The warning letter tasked the manufacturer with providing the following information in response to the warning letter:

  • A data-driven and scientifically sound analysis that identifies all sources of variability including, but not limited to, raw materials and manual steps (e.g., hand scooping). Determine the capability of each manufacturing process step and provide your corrective action and preventive action (CAPA) plan to reduce process variation.
  • A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
  • A timeline for performing appropriate process performance qualification (PPQ) for each of your [redacted] tablet drug products.
  • Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.

Common questions to consider:

Have the sources of variation been identified in the manufacturing process?

Is the process control strategy adequate?

Has post validation monitoring verified the process has remained in control?

Is there process drift? Have new sources of variation been introduced into the manufacturing process?